Download Case 1: BRCA1- and BRCA2-related ovarian cancer

Case 1: BRCA1- and BRCA2-related ovarian cancer
Janet is 58 years old and has a recent history of abdominal pain and bloating. Her primary care physician obtained a
CT scan of her abdomen and pelvis. The scan showed a pelvic mass, thickening of the omentum (fatty apron that hangs
from the colon), and fluid accumulation (ascites). Janet was referred to a gynecologic oncologist due to the concern for
a gynecologic malignancy. Her gynecologic oncologist performed surgery to remove the uterus, fallopian tubes, and
ovaries, as well as to remove the visible tumor on other surfaces and staging her cancer. The final pathology report
diagnosed stage III high-grade serous ovarian cancer.
After recovering from her surgery, Janet started the adjuvant chemotherapy that her oncologist recommended. She was
surprised that her oncologist also recommended that she undergo genetic counseling and testing. She did not think she
was at risk for an inherited susceptibility to cancer since she has no family history of breast, colon, or ovarian cancer. She
has concerns about the cost of genetic testing and the impact that it might have on her insurance status. Her 30-year-old
daughter, Susan, has been having a hard time accepting Janet’s cancer diagnosis. Janet worries that a result showing an
inherited mutation might be too overwhelming for Susan.
Fig. 1.
Janet’s pedigree, or family history tree. Often inherited patterns will show multiple family members with cancer, cancer
at young ages and cancer in several generations but one third (about 30%) of women who have ovarian cancer and an
inherited genetic risk do not have a strong family history.
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Questions
Why is Janet’s oncologist recommending genetic
counseling and testing for her?
All women with epithelial ovarian, fallopian tube, and
primary peritoneal cancer have been recommended to
undergo genetic counseling and testing since the National
Comprehensive Cancer Network (NCCN) issued its 2011
guidelines. The Society of Gynecologic Oncology (SGO)
has endorsed that recommendation. It is based on data
that about 20 percent of women with these cancers carry
an inherited mutation in BRCA1, BRCA2, MSH2, MLH1,
MSH6, PMS2, EPCAM, BRIP1, RAD51C, RAD51D, PALB2,
and/or BARD1. Increased hereditary risk is associated
with young age at diagnosis, family history of breast and/
or ovarian cancer, and some ethnicities such as Ashkenazi
Jewish ancestry. These factors do not need to be present in
order to make testing reasonable since at least one third of
women with hereditary ovarian cancer have none of these
risk factors. All histologic types of invasive (not borderline)
epithelial ovarian cancers should prompt consideration
for referral to genetic counseling and testing. Mucinous
ovarian cancer represents a rare exception since it has not
been routinely shown to be part of hereditary breast and
ovarian cancer or Lynch syndromes. Genes that increase
the risk of breast cancer as well as ovarian cancer are part
of hereditary breast and ovarian cancer (HBOC) syndrome.
Those genes that increase the risk of colon, endometrial
and ovarian cancer are associated with Lynch syndrome.
What types of genetic tests are available to Janet?
Traditionally, genetic testing has been performed one or
two genes at a time, starting with the gene(s) considered
most likely to be involved based on the patient’s personal
and family history. The testing looks for germline changes
(mutations) in genes, meaning that they are in every cell
and can be passed on to children. This process can be
expensive and time-consuming if multiple genes could
be involved. Recently, multi-gene panel tests have been
developed that include anywhere from a handful to several
dozen cancer predisposition genes. These panels have
the advantage of testing for many potential gene mutations
simultaneously at a lower cost than traditional testing.
Because so many genes in a panel are being investigated,
however, there is also a higher likelihood of diagnosing a
variant of uncertain significance (VUS), which is a genetic
change without any clear association to a health problem.
Changes in a gene that are known to be associated with a
health problem like cancer are called deleterious mutations
or pathogenic variants.
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Clinical recommendations like enhanced cancer screening
or risk-reducing surgery are reserved for those individuals
who are found to have a deleterious mutation or who have
a strong family cancer history, because most VUS are
ultimately found not to be associated with health problems
and medical decisions should not be based on the
presence of a VUS. The decision to pursue gene-by-gene
testing versus panel testing is a complex one that benefits
from discussion with a genetics professional. In addition to
germline testing, patients may also benefit from having the
tumor itself tested for mutations. Mutations that occur in the
tumor are called somatic mutations and cannot be passed
through the family (unlike germline mutations). Knowledge
of either germline or somatic mutations may help
direct treatment.
How might the genetic test results affect Janet’s
treatment? Would they affect her eligibility for
clinical trials?
Janet’s treatment might be affected in several ways if
she is found to have a gene mutation. If she was found to
have a BRCA1 or BRCA2 mutation, for example, and her
ovarian cancer goes into remission, she might choose to
receive enhanced breast cancer screening. Survival from
ovarian cancer is improved in women who have a BRCA1
or BRCA2 mutation compared with those who do not
have a mutation, and BRCA1- and BRCA2-related ovarian
cancer may be more sensitive to platinum chemotherapy.
This may affect treatment options for her. If her ovarian
cancer recurs, she might be eligible for treatment with a
class of drugs called PARP inhibitors that are particularly
effective in women with BRCA1 and BRCA2 mutations.
Currently, the PARP inhibitor, olaparib, is FDA-approved
in the United States for women with recurrence of ovarian
cancer after three previous lines of therapy if they carry
a germline BRCA1 or BRCA2 mutation. However, clinical
trials with PARP inhibitors might be available for women
in other clinical settings, such as mutations in genes other
than BRCA1and BRCA2, fewer prior treatment regimens, or
somatic mutations in their tumor rather than in the germline.
References
B.M. Norquist, M.I. Harrell, M.F Brady, T. Walsh, M.K. Lee, S. Gulsuner, et al. Inherited mutations in women with ovarian carcinoma.
JAMA Oncol. 2 (4) (2016). 482-490.
Angelina Jolie Pitt: My Medical Choice (New York Times, May 14, 2013).
Angelina Jolie Pitt: Diary of a Surgery (New York Times, March 24, 2015).
National Comprehensive Cancer Network
J.M. Lancaster, C.B. Powell, L. Chen, D. L. Richardson; SGO Clinical Practice Committee. Society of Gynecologic Oncology
statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 136 (1) (2015) 3-7.
Society of Gynecologic Oncology Clinical Practice Statement: Next Generation Cancer Gene Panels versus Gene by Gene Testing,
March 2014.
How is Ovarian Cancer Staged? American Cancer Society. Accessed 4/7/16.
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